Mechanochemical mechanism underlying intercellular Ca2+ wave propagation and its crucial role in apoptotic cell extrusion

Calcium (Ca²⁺) wave propagation plays a crucial role in intercellular communication. Elevation of cytosolic Ca²⁺ (Ca²⁺ transient) in a single cell is attributed to various Ca²⁺ channels present in the plasma membrane and endoplasmic reticulum, whereas gap junctions contribute to propagation of Ca²⁺ waves between cells. However, we found that Ca²⁺ waves propagate without gap junctions during apoptotic cell extrusion (ACE). Mechanistically, we identified that a chain reaction of mechano-signal transduction from proximal to distal cells through the mechanosensitive Ca²⁺ channels (MCCs) mediates the Ca²⁺ wave propagation; an apoptotic cell shrinks accompanied by a Ca²⁺ transient, followed by pulling the edges of neighboring cells, which opens MCCs in neighboring cells, resulting in Ca²⁺ transients in these cells. Furthermore, Ca²⁺ wave propagation promotes Rac-Arp2/3 pathway-mediated polarized collective migration, generating approximately 1 kPa of force toward extruding cells. Our results uncovered a mechanochemical mechanism of Ca²⁺ wave propagation and its significant role in ACE.